Azatetracycle compounds

ABSTRACT

An azatetracycle compound useful as 5HT 3  antagonists of the general formula ##STR1## wherein D is a tetracycle of the structure ##STR2## wherein Ar is an aromatic moiety and B is either NH or O.

This application is a .Iadd.reissue of Ser. No. 07/682,993 filed Apr.12, 1991, now U.S. Pat. No. 5,140,023 which is a.Iaddend.continuation-in-part of U.S. patent application Ser. No.07/515,391 filed Apr. 27, 1990, now abandoned.

BACKGROUND OF THE INVENTION

The invention herein is directed to azatetracycle compounds of thegeneral formula ##STR3## wherein A can be NH or a covalent bond, whereinp can be 1 or 0, Ar represents an aromatic moiety as will hereinafter befurther discussed, B represents NH or O and D represents the tetracyclicstructure ##STR4## or

The azatetracylic compounds of the present invention are useful in thetreatment of gastrointestinal motility disorders such asgastroesophageal reflux, non-ulcer dyspepsia, delayed gastric emptying,ileus, irritable bowel syndrome, and the like. Further, the compounds ofthe present invention exhibit 5-HT₃ antagonist activity making thecompounds useful as 5-HT₃ antagonists. The compounds are thereforeuseful as antiemetics, analgesics, anxiolytics, and exhibit utility inthe treatment of substance abuse, schizophrenia, depression, andmigraine headaches, presenile and senile dementia (i.e., Alzheimer'sdisease and senile dementia of the Alzheimer type), and enhancers ofintra-nasal absorption of bioactive compounds.

Aza-adamantyl compounds are disclosed in U.S. Pat. No. 4,816,453 and arementioned generically in: U.K. Patent 2,152,049A; European application0189002A2; and U.K. Patent 21,169,292B.

Azabicyclic nonanes are disclosed in European Patent application0094742A2. Additional azabicyclic compounds are disclosed in: U.S. Pat.No. 4,797,387; European application 323,077A; European Patent 0230718A1;J. Med. Chem. (1987) 30,1535; Australian Patent 8767121; European Patent0094742A2; Australian Patent 8207867; and European Patent 031539082. Inaddition general azabicyclic systems are disclosed in the followingPatents: European Patent 0076592A2; U.K. Patent 2166726A; EuropeanPatent 0201165A2; European Patent 0220011A2; U.S. Pat. Nos. 4,336,259;4,273,778; and 4,797,406.

SUMMARY OF THE INVENTION

The invention herein is directed to azatetracyclic compounds of thegeneral formula ##STR5## wherein D can be ##STR6## wherein B can be NHor O; wherein A can be NH or a bond;

wherein p can be 1 or 0; and

when p is 1, Ar can be ##STR7## and when p is 0, Ar can be ##STR8##wherein X can be O,S,N,(R⁴) or CH₂ ; wherein Y can be N or CH;

wherein n is 1 or 2;

wherein Z can be ##STR9## wherein R¹ can be alkoxy of 1 to 6 carbonatoms; wherein R² and R³ are the same or different and can be hydrogen,halogen, CF₃, hydroxyl, C₁₋₂ alkoxy, C₂₋₇ acyl, amino, amino substitutedby one or two C₁₋₆ alkyl groups, C₂₋₇ acyl amino, amino carbonyl, oramino sulfone optionally substituted by one or two C₁₋₆ alkyl groups,C₁₋₆ alkyl sulfone or nitro groups;

wherein R⁴ and R^(4') can be the same or different and can be hydrogen,alkyl or arylalkyl;

wherein R⁵ and R⁶ can be the same or different and can be hydrogen,halogen, CF₃, C₁₋₆ alkyl, C₁₋₇ acyl, C₁₋₇ acylamino, or amino, aminocarbonyl or amino sulfonyl, optionally substituted by one or two C₁₋₆alkyl or C₃₋₈ cycloalkyl groups, or by C₄₋₅ polymethylene or biphenyl,C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio,hydroxy or nitro or when R⁵ and R⁶ are taken together are methylenedioxyor ethylenedioxy;

wherein R⁹ and R¹⁰ can be the same or different and can be hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₄ alkynyl or together are C₂₋₄polymethylene;

wherein R⁷ and R⁸ are the same or different and can be hydrogen,halogen, CF₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₇ acyl, C₁₋₇acylamino, C₁₋₆ alkylsulfonylamino, N-(C₁₋₆ alkylsulfonyl)-N-C₁₋₄alkylamino, C₁₋₆ ALKYLSULFINYL, hydroxy, nitro or amino, aminocarbonyl,aminosulfonyl, aminosulfonylamino or N'-(aminosulfonyl)-C₁₋₄ alkylaminooptionally N-substituted by one or two groups selected from C₁₋₆ alkyl,C₃₋₈ cycloalkyl, phenyl, or phenyl C₁₋₄ alkyl groups or OptionallyN'-disubstituted by C₄₋₅ polymethylene; and

wherein R¹¹ and R¹² can be the same or different and can be hydrogen orC₁₋₄ alkyl or taken together are a covalent bond and R¹³ can be H,halogen or OR⁴.

DETAILED DESCRIPTION

The azatetracyclic compounds that are the subject of the inventionherein can be prepared in the following reaction Schemes I and II. Inreaction Scheme I a method of producing azatetracyclic benzamides isshown and in reaction Scheme II a method for producing azatetracyclicamines is shown. ##STR10## Referring to reaction Scheme I,trans-1,2-di-carbomethoxy-4-methylene-cyclopentane is reacted withsodium hydroxide followed with acid to producetrans-4-methylene-1,2-cyclopentanedicarboxylic acid. The dicarboxylicacid is reacted with acetic anhydride to producecis-tetrahydro-5-methylene-1H-cyclopenta c!furan-1,3(3aH)-dione. Theammonium salt 4 is prepared by reacting the anhydride 3 in dry methylenechloride with ammonia gas. The imide 5 is prepared from the ammoniumsalt by reacting the ammonium salt with acetyl chloride. The imide isreacted with lithium aluminum hydride and ditertiarybutyl dicarbonate toproduce cis-1,1-dimethylethylhexahydro-5-methylenecyclopentac!pyrrole-2(1H)carboxylate 6. The term BOC is used herein to refer tot-butyloxy carbonyl. The BOC-amine 6 is reacted withbis(p-toluenesulfonyl) sulfodiimide to produce the p-toluenesulfonamide7. The term Tos is used herein to represent p-toluenesulfonyl. Thep-toluenesulfonamide is reacted with thexyl borane to produce the endoalcohol 8. The endo alcohol is reacted with p-toluenesulfonyl chlorideto produce the tosylate 9. The tosylate 9 is reacted withtrifluoroacetic acid and treated with Hunig's base to provide thep-toluenesulfonamide tetracycle 10. The sulfonamide tetracycle 10 wasreductively cleaved to produce the aminoazatetracycle 11. Coupling ofthe aminoazatetracycle 11 with benzoic acid derivative 12 under mixedanhydride conditions gave the protected benzamide tetracycle 13. Basichydrolysis of the acetamide 13 gives the benzamide tetracycle 14 whichupon treatment with HCl produces the hydrochloride salt of the benzamidetetracycle 15.

A more detailed description of the process shown in Scheme I is setforth in the following Examples 1-12.

EXAMPLE 1 trans-4-methylene-1,2-cyclopentanedicarboxylic acid 2

A diester, trans-1,2-di-carbomethoxy-4-methylenecyclopentane, (1.48g,7.47 mmol) prepared by the method of Trost (J. Am. Chem. Soc. 105 2315(1983) was heated under reflux for 2 hours with 2N sodium hydroxide (11ml, 22 mmol). The resulting solution was cooled in an ice bath andacidified with concentrated (37%) hydrochloric acid (8.0 ml) until a pHof 0.6 was attained. The resulting slurry was filtered, washed withwater, and dried in vacuo to give the diacid 2 (0.987g, 77.7%) as acolorless powder: mp 178°-179° C.; Anal. calcd for C₈ H₁₀ O₄ : C, 56.47;H, 5.92. Found: C, 56.08; H, 5.87.

EXAMPLE 2 cis-tetrahydro-5-methylene-1H-cyclopentac!furan-1,3(3aH)-dione 3

A suspension of the diacid 2 (689 mg, 4.05 mmol) from Example 1 infreshly distilled acetic anhydride (7 ml) was heated for 4 hours at 100°C. The majority of acetic anhydride was removed by distillation and theremainder was removed under a stream of nitrogen leaving a residue whichwas distilled (170°-175° C. at 1 mm Hg) giving the desired anhydride 3(175 mg, 28%) as an oil which crystallized on standing: mp 50°-51° C.;Anal. calcd for C₈ H₈ O₃ : C, 63.15; H, 5.30. Found: C, 62.91; H, 5.43.

EXAMPLE 3 cis-4-methylene-2-carboxamidocyclopentane-1-carboxylic acid,ammonium salt

Into a solution of anhydride 3 from Example 2 (14.6 g, 95.9 mmol) inchloroform (900 ml) was bubbled ammonia gas for 2 hours. The resultingsuspension was filtered, washed with chloroform and dried to give theammonium salt 4 (11.64 g, 65.2%) as a colorless powder: mp 158°-160° C.(dec); Anal. calcd for C₈ H₁₄ N₂ O₃ : C, 51.60; H, 7.58; N, 15.04.Found: C, 51.45; H,7.51; N, 14.79.

EXAMPLE 4 cis-tetrahydro-5-methylenecyclopentac!pyrrole-1,3(2H,3aH)-dione 5

A suspension of ammonium salt 4 from Example 3 (2.18g, 11.7 mmol) infreshly distilled acetyl chloride (40 ml) was heated under reflux for 22hours. The resulting solution was concentrated under a stream ofnitrogen, then in vacuo, to give a dark oil which was dissolved inmethanol (10 ml) and treated with ammonia-saturated methanol (10 ml) andstirred for 3.5 hours. The solution was concentrated under a stream ofnitrogen to give an oil which was chromatographed on silica gel elutingwith ethanol/methylene chloride (1/99, then 2/98) to give the imide 5(1.46g, 82.6%) as a colorless solid which was recrystallized fromchloroform/hexane to give the desired imide 5 (1.21g) as colorlessneedles; mp 135°-137° C. (softens at 133° C.). Anal. calcd for C₈ H₉ NO₂: C, 63.56; H, 6.00; N, 9.27. Found: C, 63.60; H, 6.03; N, 9.12.

EXAMPLE 5 cis-1,1-dimethylethylhexahydro-5-methylenecyclopentac!pyrrole-2(1H)-carboxylate (BOC amine 6)

To a solution of lithium aluminum hydride (11.8 ml of a 1M solution inTHF) was added a solution of the imide 5 from Example 4 (1.19g, 7.89mmol) in dry THF (26 ml) dropwise via syringe. After the addition wascomplete the reaction was stirred for 11/2 hours at room temperature,then heated under reflux for 2 hours. After cooling to room temperaturethe reaction was quenched with the addition of 0.45 ml H₂ O followed bythe addition of 0.45 ml of 15% NaOH then 1.35 ml of H₂ O. The solidswere removed by filtration and rinsed with dry THF (11×10 ml) giving asolution which was treated immediately with di-tert-butyl dicarbonate(1.89 g, 8.68 mmol). The solution was stirred under argon for 5 days atroom temperature and concentrated under a stream of nitrogen to give anoil which was purified by chromatography eluting with ethylacetate/hexane (5/95, then 10/90) to give the desired BOC amine 6 (1.34g, 76%) as a colorless oil: Anal. calcd for C₁₃ H₂₁ NO₂ : C, 69.92; H9.48; N, 6.27. Found: C, 69.03; H, 9.47; N, 6.20 Ms: calcd for C₁₃ H₂₁NO₂, 223.1572; Found, 223.1578.

EXAMPLE 6 1,1-dimethylethylhexahydro-5-methylene-4β-(4-methylphenyl)sulfonyl!amino!-3aβ,6aβ-cyclopentac!pyrrole-2(1H)-carboxylate (p-toluenesulfonamide 7)

To a solution of the BOC amine 6 (78.4 mg, 0.35 mmol) from Example 5 indry dichloromethane (2 ml) was added bis(p-toluenesulfonyl) sulfodiimide(134 mg, 0.362 mmol) prepared by the method of Wucherpfennig and Kresze,Tet. Lett 1671 (1966). The resulting solution was stirred for 18 hoursat room temperature and concentrated in vacuo to give a pale yellow foam(224 mg). A 116 mg portion of the 224 mg was treated directly with 1.3ml of a solution made from 2.4 g K₂ CO₃, 12 ml MeOH, and 8 ml H₂ O.After 14 hours at room temperature, the reaction was diluted withdiethyl ether (6 ml) and washed with 2:1 l N NaOH: brine (1.5 ml), waterand brine. The resulting solution was dried with MgSO₄ and concentratedin vacuo to give a crystalline solid (54.8 mg). Recrystallization fromcarbon tetrachloride/hexane gave the desired p-toluenesulfonamide 7 (37mg, 51%) as colorless crystals: mp 166.5°-168° C.; MS: calcd for C₂₀ H₂₈N₂ O₄ S: 392; Found: 392. Anal. calcd for C₂₀ H₂₈ N₂ O₄ S. 0.25 H₂ O:C,60.50; H, 7.24; N, 7.06; S,8.08. Found: C, 60.42; H, 7.10; N, 6.98; S,8.24.

EXAMPLE 7 1,1-dimethylethylhexahydro-5α-(hydroxymethyl)-4β-(4-methylphenyl)sulfonyl!amino!-3aβ,6aβ-cyclopentac!pyrrole-2(1H)-carboxylate (Endo alcohol 8)

To a solution of borane in THF (1.82 ml of a 1M solution 1.82 mmol) at0° C. was added dropwise a solution of 2,3-dimethyl-2-butene (1.82 ml ofa 1M solution, 1.82 mmol). The resulting solution was stirred for 2hours at 0° C. To this solution of thexyl borane at 0° C. was added asolution of p-toluenesulfonamide 7 (230 mg, 0.586 mmol) from Example 6in dry THF (3 ml) and the resulting solution was stirred for 20 hours atroom temperature. The reaction was cooled to 0° C. and quenched with 10%NaOH (0.91 ml) followed by 30% H₂ O₂ (0.76 ml) and stirred for 1/2 hourat 0° C., then 1 hour at room temperature. After concentrating under astream of nitrogen, water (4 ml) was added and the mixture was extractedwith diethyl ether (3×). The combined organic extracts were washed withwater (5×) and brine. The solution was dried over Na₂ SO₄ andconcentrated in vacuo to give a residue (297 mg) which waschromatographed on silica gel eluting with ethanol/methylene chloride(1.5/98.5) to give the desired alcohol 8 (92 mg, 38%) as a colorlessglass: mp 50°-60° C.; MS: MH⁺ Calcd for C₂₀ H₃₀ N₂ O₅ S, 411; Found 411;Calcd for C₁₆ H₂₁ N₂ O₅ S (M-Bu^(t)), 353.1171; Found 353.1158. Anal.calc for C₂₀ H₃₀ N₂ O₅ S.1/4 H₂ O: C, 57.88; H, 7.41; N, 6.75; S, 7.73.Found: C, 57,89; H, 7.45; N, 6.75; S, 7.71.

EXAMPLE 8 1,1-dimethylethylhexahydro-5α-(4-methylphenyl)sulfonyl!oxymethyl!-4β-(4-methylphenyl)sulfonyl!amino!-3aβ,6aβ-cyclopentac!-pyrrole-2(1H)-carboxylate (tosylate 9)

A solution of alcohol 8 (356 mg, 0.867 mmol) from Example 7 in drypyridine (6 ml) was treated with p-toluene sulfonyl chloride (496 mg,2.60 mmol) and the resulting solution was allowed to stand at 0° C. for45 hours. The reaction mixture was poured onto ice (12 g) and extractedwith diethyl ether (3×). The combined organic phases were dried overMgSO₄. Concentration in vacuo gave the desired tosylate 9 (470 mg, 96%)as a foam: mp 54°-67° C. Anal. calcd for C₂₇ H₃₆ N₂ O₇ S₂ : C, 57.43; H,6.42; N, 4.96; S, 11.35. Found: C, 56.72; H, 6.34; N, 4.94; S, 11.18.

EXAMPLE 9 4-methyl-N-(hexahydro-1H-2,5β-methano-3aα,6aα-cyclopentac!pyrrole-4α-yl)benzenesulfonamide (p-Toluenesulfonamide Tetracycle 10)

To the tosylate 9 (456 mg, 0.807 mmol) from Example 8 in a flask cooledin an ice bath was added freshly distilled trifluoroacetic acid (2.0ml). The resulting solution was allowed to warm to room temperature over20 min. and concentrated in vacuo to give a foam (499 mg) which wasdissolved in freshly distilled acetonitrile (16 ml) and treated withHunig's base (417 mg, 3.23 mmol). The solution was stirred for 20 hoursat 45°-50° C. After concentration in vacuo, a concentrated aqueoussolution of KOH (13 ml) was added and the mixture was extracted withchloroform (5×). The combined organic extracts were washed with brineand dried over sodium sulfate. Concentration in vacuo gave a residuewhich was chromatographed on silica gel eluting with ammonia-saturatedmethanol/chloroform (3/97) to give the desired tetracycle 10 (149 mg,65%) as a colorless powder: mp 199°14 200° C. (dec.). Anal. calcd forfor C₁₅ H₂₀ N₂ SO₂ : C, 61.62; H, 6.89; N, 9.58; S, 10.96. Found: C,61.65; H, 6.96; N, 9.53; S, 11.29.

EXAMPLE 102-Methoxy-4-acetamido-5-chloro-N-(hexahydro-1H-2,5β-methano-3aα,6aα-cyclopentac!pyrrol-4α-yl)benzamide (Benzamide Tetracycle 13)

To a solution of sulfonamide 10 (26 mg, 0.089 mmol) from Example 9 inTHF/ammonia (1:1, 6 ml) at -78° C. was added sodium metal (ca. 20 mg).The resulting blue solution was warmed to -33° C. over several minutesand quenched with solid NH₄ Cl (160 mg, 3.0 mmol). The mixture wasconcentrated under a stream of nitrogen leaving a white solid to whichwas added triethylamine and dimethylformamide (0.8 ml) plus water (1ml). Concentration in vacuo gave the crude deprotected aminoazatetracycle 11, N-(hexahydro-1H-2,5β-methano-3aα,6aα-cyclopentac!pyrrol-4α-yl)amine.

To a solution of benzoic acid derivative 12,2-methoxy-4-acetamido-5-chlorobenzoic acid, (23.8 mg, 0.098 mmol) in dryDMF (0.2 ml) was added N-methylmorpholine (11 mg, 0.11 mmol). Theresulting solution was cooled to 0° C. and isobutylchloroformate (13 mg,0.098 mmol) was added. After 1/2 hour at 0°C. the crude deprotectedamino azatetracycle 11 was added as a suspension in DMF/triethylamine(1:1, 1.5 ml). The reaction was warmed to 50° C. for 14 hour. Aftercooling to room temperature, 1N KOH (3.0 ml) was added. The solution wasconcentrated in vacuo to give a white solid (303 mg) which was dissolvedin 2N KOH (1 ml) and extracted with chloroform (5×). The combinedextracts were washed with water and brine and dried over Na₂ SO₄Concentration under a stream of nitrogen gave an oil (28 mg) which waschromatographed on silica gel. Eluting with methanol (saturated withNH₃)/chloroform (3/97) gave the desired benzamide tetracycle 13 as aglass (8.5 mg, 26%). MS calc for C₁₈ H₂₂ N₃ O₃ Cl: 363.1244; Found:363.1247.

EXAMPLE 112-methoxy-4-amino-5-chloro-N-(hexahydro-1H-2,562-methano-3aα,6a.alpha.-cyclopentac!-pyrrol-4α-yl)benzamide 14

To a solution of acetamide 13 (8.5 mg, 0.023 mmol) from Example 10 inethanol (1.5 ml) was added potassium hydroxide (7.7 mg, 0.14 mmol) andthe mixture was heated to reflux for 2.5 hours. The resulting solutionwas cooled and concentrated under a stream of nitrogen to give a residuewhich was chromatographed on silica gel eluting with ammonia-saturatedmethanol/chloroform (3/97) to give the desired compound 14 (5.8 mg, 79%)as a glass: MS calculated for C₁₆ H₂₀ N₃ O₂ Cl 321.1244; Found 321.1247.¹ H NMR (300 MHz, CDCl₃) δ8.09 (1H, s), 7.66 (1H, d, J=6 Hz), 6.28 (1H,s), 4.37 (3H, m), 3.88 (3H, s), 3.21 (1H, dd, J=11, 2.6 Hz), 3.05 (1H,dd, J=11, 2.6 Hz), 3.0-2.8 (4H, m), 2.63 (1H, m), 2.56 (1H, m) 2.16 (1H,m), 2.1-1.97 (1H, m), 1.9 (1H, m). ¹³ C NMR (CDCl₃) 163.3 157.3, 146.5,133.1, 112.8, 111.8, 97.8, 66.5, 65.0, 62.1, 57.4, 56.2, 45.6, 42.2,39.2, 37.6 ppm.

EXAMPLE 122-methoxy-4-amino-5-chloro-N-(hexahydro-1H-2,5B-methano-3aα,6aα-cyclopentac!pyrrol-4α-yl)benzamidehydrochloride 15

To the free base 14 (3 mg) from Example 11 dissolved in methanol (0.2ml) at 5° C. was added HCl/methanol (0.5 ml). The resulting solution wasconcentrated under a stream of nitrogen, dissolved in water, frozen, andlyophilized to give the desired hydrochloride salt 15 (2.7 mg): MS calcdfor C₁₆ H₂₀ N₃ O₂ Cl, 321.1244, Found, 321.1245. ¹ H NMR (300 MHz,d4-methanol) δ7.74 (1H, s), 6.54 (1H, s), 4.35 (1H, s), 3.89 (3H, s),3.71 (1H, dd, J=11, 1.6 Hz), 3.6-3.4 (5H, m), 3.08-2.95 (2H, m), 2.61(1H, br s), 2.23-2.12 (1H, m), 2.06 (1H, d, J=13 Hz). ¹³ C NMR(d4-methanol) δ 166.7, 159.3, 150.0, 132.8, 111.8, 111.4, 98.7, 64.5,63.5, 61.8, 56.7, 56.0, 43.6, 41.2, 37.5, 36.8 ppm.

EXAMPLE 12A(±)-4-amino-5-chloro-N-(hexahydro-2,5β-methano-1H-3aα,6a.alpha.-cyclopentac!pyrrol-4α-yl)-2-ethoxybenzamide, hydrochloride ##STR11##

To a solution of 2-ethoxy-4-acetamido-5-chlorobenzoic acid (106 mg, 0.41mmol) in DMF (1 ml) was added carbonyldiimidazole (67 mg, 0.41 mmol).After stirring for 6h at room temperature a solution of theazatetracycle 11 from Example 18 (57 mg, 0.41 mmol) in DMF (2 ml) wasadded dropwise and the reaction was stirred for 34 h at roomtemperature. A solution of potassium carbonate (340 mg) in brine (5 ml)was added and the solution was extracted with chloroform (5×). Thecombined organic extracts were washed with water and brine, dried oversodium sulfate, and concentrated in vacuo to give a colorless foam (178mg). This residue was chromatographed on silica gel eluting withethanol/chloroform/ammonium hydroxide (9.5/90/0.5) to give the desiredamide (120 mg, 77%) as a colorless powder. MS calcd for C₁₉ H₂₄ N₃ O₃ Cl377.1506, found 377.1511.

A solution of this acetamide (117 mg) and potassium hydroxide (107 mg,I.9 mmol) in ethanol (I6 ml) was then heated under reflux for 2 h. Thesolution was then concentrated to a residue which was suspended in 20 mlof water and filtered to give the title compound (89 mg, 86%) as thefree base. This amide in methanol (0.5 ml) was treated with HCl/methanolprepared from acetyl chloride (19 mg, 0.27 mmol) and methanol (0.5 ml)!.The resulting salt was crystallized from methanol/diethyl ether to givethe title compound (88 mg) as a colorless powder: mp 263°-264° C. Anal.calcd for C₁₇ H₂₂ N₃ O₂ Cl..1.1HCl.H₂ O: C, 51.83; H, 6.42; N, 10.67;Cl, 18.90. Found: C, 51.68; H, 6.15; N, 10.69; Cl, I8.61. MS calcd forC₁₇ H₂₂ N₃ O₂ Cl: 335.1400; found: 335.1414.

EXAMPLE 12B(±)-4-dimethylamino-5-chloro-N-(hexahydro-2,5β-methano-1H-3aα,6aα-cyclopentac!pyrrol-4α-yl)-2-methoxybenzamide, hydrochloride ##STR12##

To a solution of 2-methoxy-4-dimethylamino-5-chlorobenzoic acid (67 mg,0.29 mmol) in DMF (0.5 ml) was added carbonyldiimidazole (47 mg, 0.29mmol). After stirring for 2h at room temperature a solution of theazatetracycle 11 from Example 18 (40 mg, 0.29 mmol) in DMF (1 ml) wasadded dropwise and the reaction was stirred for 24 h at roomtemperature. After the reaction mixture was concentrated in vacuo aconcentrated aqueous solution of potassium carbonate was added and themixture was extracted with chloroform (3×). The combined organicextracts were washed with water (2×) and brine, dried over sodiumsulfate, and concentrated in vacuo to give a colorless solid (177 mg).This residue was chromatographed on silica gel eluting with methanol(saturated with NH3)/chloroform (3/97) to give the desired amide 66 mg,65%) as a colorless powder. This amide in methanol (0.5 ml) was treatedwith HCl/methanol prepared from acetyl chloride (13 mg, 0.19 mmol) andmethanol (0.5 ml)!. The resulting salt was crystallized frommethanol/diethyl ether to give the title compound (64 mg) as a colorlesspowder: mp 216°-217° C. Anal. calcd for C₁₈ H₂₄ N₃ O₂ Cl,HCl: C, 55.96;H, 6.62; N, 10.88; Cl, 18.35. Found: C, 55.60; H, 6.35; N, 10.54; Cl,17.94. MS M+1 calcd for C₁₇ H₂₂ N₃ O₂ Cl: 350; found: 350. ##STR13##

The process of Scheme II can be understood with respect to the followingdiscussion. An allyl iodomalonate 16 and N--BOC allylic amine 17 arereacted photolytically to provide azabicyclic malonate 18. The malonate18 is reacted to produce an unsaturated ester 19. The ester 19 isreduced to provide an allylic alcohol 20 with which its correspondingtrichloroimidate is thermally rearranged to give trichloroacetamide 21.The trichloroacetamide 21 is reacted with borane and oxidized withhydrogen peroxide to form the alcohol 22. The alcohol 22 is reacted withp-toluenesulfonyl chloride to produce crude tosylate which isdeprotected with trifluoroacetic acid and cyclized in the presence ofHunig's base to yield the tetracycle 11.

Further details of the process shown in Scheme II are exemplified in thefollowing examples 13-18.

EXAMPLE 132-(1,1-dimethylethyl)-5,5-dimethyl-3aβ,6aβ-hexahydrocyclopentac!pyrrole-2,5,5(1H,4H)-tricarboxylate 18 ##STR14##

To a solution of 1.27 g (4.26 mmol) of2-iodo-2-(2'-propen-1-yl)dimethylmalonate (allyl iodomalonate) 16 (ref.Curran, D. P.; Chen, M.-H.; J. Am. Chem. Soc. 1989, vol. 111, p 8872)and 1.34 g (8.52 mmol) of N-butoxycarbamoylallylamine (N-BOC allylicamine) 17 in 10 mL of benzene was added via syringe 0.16 mL ofbis(tributyltin). After exposing the clear homogeneous solution to lightfrom a sunlamp (d=8 cm) for 30 min, the light source was removed and 5mL of triethylamine was added. The solution was heated at reflux for 20hours at which time the dark brown-red mixture was concentrated underreduced pressure. Flash chromatography on 150 g of silica gel (ethylacetate:hexane, 1:5 to 1:3) provided 0.61 g of azabicycle 18 as a clearoil. MS: C₁₆ H₂₅ NO₆ M⁺ 327. Anal. calcd for C₁₆ H₂₅ NO₆ : C, 58.69; H,7.71; N, 4.28; found: C, 57.87; H, 7.62; N, 4.07.

EXAMPLE 14 2-(1,1-dimethylethyl)-5-methyl-3,3aβ,6aβ-tetrahydrocyclopentac!pyrrole-2,5(1H)-dicarboxylate 19 ##STR15##

A solution of 8.0 g (24.4 mmol) of azabicycle diester 18 from Example 13and 1.34 g (26.9 mmol) of sodium cyanide in 100 mL dimethylsulfoxide washeated to 160° C. for 5.5 hours. The mixture was cooled and poured into4000 mL of water. The solution was extracted with ether (5×2400 mL). Theorganic extracts were combined, washed with water (4×1000 mL), driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure to provide 4.81 g of diastereomeric esters as ared-brown oil. This product was used without further purification.

To a solution of 3.36 mL (23.9 mmol) of diisopropylamine in 125 mL oftetrahydrofuran at -78° C. was added via syringe 14.4 mL of a 1.55 Msolution of n-butyllithium in hexane. After stirring for 5 min, asolution of 4.81 g (17.9 mmol) of diastereomeric esters and 14.3 mL ofhexamethylphosphoramide in 75 mL of tetrahydrofuran was added viacannula. The brown solution was stirred at -78° C. for 40 min at whichtime a solution of 7.2 g (22.3 mmol) of diphenyl diselenide in 50 mL oftetrahydrofuran was added. The resulting red solution was warmed to 0°C. and stirred for 2.5 hours. The solution was poured into 900 mL of asaturated aqueous solution of ammonium chloride and extracted with ether(4×200 mL). The organic extracts were combined, dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure toprovide 8.72 g of an orange-red oil. Chromatography on a Waters Prep 500system (ethyl acetate:hexane, 15:85; flow rate 200 mL/min) afforded 4.74g of diastereomeric selenides as a yellow oil.

To a solution of 4.74 g (11.2 mmol) of diastereomeric selenides in 175mL of dichloromethane at -78° C. was added in small portions 2.89 g(16.8 mmol) of m-chloroperbenzoic acid. The suspension was stirred at-78° C. for 2 hours. Dimethyl sulfide (1 ml) was added and thesuspension was stirred at -78° C. for an additional hour. After adding0.5 mL of pyridine, the cold suspension was directly added via cannulato 500 mL of refluxing carbon tetrachloride. The yellow homogeneoussolution was refluxed for 2 min, cooled to room temperature in an icebath, and poured into 800 mL of a saturated aqueous solution of ammoniumchloride containing 15 g of potassium carbonate. The mixture wasextracted with dichloromethane (4×150 mL). All organic extracts werecombined, dried over anhydrous potassium carbonate, filtered, andconcentrated under reduced pressure to give 6.77 g of a yellow oil.Chromatography on a Waters Prep 500 system (ethyl acetate:hexane, 15:85to 25:75; flow rate 200 mL/min) produced 2.02 g of unsaturated ester 19as an oil. ¹ H NMR (CDCl₃) δ3.76 (3H, s), 6.61 (1H, br s); ¹³ C NMR(CDCl₃) 136.2, 144.8, 154.0, 165.3 ppm.

EXAMPLE 152-(1,1-dimethylethyl)-5-hydroxymethyl-3,3aβ,6,6aβ-tetrahydrocyclopentac!pyrrole-2(1H)-carboxylate 20 ##STR16##

To a solution of 1.96 g (7.32 mmol) of unsaturated ester 19 from Example14 in 60 mL of dichloromethane at -78° C. was added via syringe 18.3 mLof a 1.0M solution of diisobutylaluminum hydride in dichloromethane. Thesolution was stirred at -78° C. for 90 minutes. The solution wasquenched at -78° C. with 1 mL of methanol and poured into 800 mL of asaturated aqueous solution of Rochelle's salt. After stirring overnight,the mixture was extracted with dichloromethane (4×150 mL). The organicextracts were combined, dried over anhydrous potassium carbonate,filtered, and concentrated under reduced pressure to afford 1.75 g of apale yellow oil. Flash chromatography on 210 g of silica gel (ethylacetate:hexane, 1:1) provided 1.5 g of the above alcohol 20 as an oil. ¹H NMR (CDCl₃) δ4.17 (2H, br s), 5.50 (1H, br s); ¹³ C NMR (CDCl₃) 60.5,126.6, 143.1, 153.7 ppm.

EXAMPLE 16 1,1-dimethylethylhexahydro-5-methylene-4β- (trichloroacetyl)amino!-3aβ,6aβ-cyclopenta- c!pyrrole-2(1H)-carboxylate 21 ##STR17##

To a suspension of 25 mg (0.63 mmol) of sodium hydride in 11 mL of etherwas added a solution of 1.01 g (4.2 mmol) of alcohol 20 from Example 15in 4 mL of ether. After stirring for 5 min, the pale yellow solution wascooled to 0° C. and treated with 0.44 mL (4.41 mmol) oftrichloroacetonitrile. The resulting brown-yellow homogeneous solutionwas stirred at 0° C. for 15 min, warmed to room temperature, and stirredfor 30 min. The mixture was concentrated under reduced pressure. Theresulting brown oil was shaken for 1 min in 50 mL of pentane containing0.06 mL of methanol. The suspension was filtered and concentrated underreduced pressure to give 1.3 g of imidate as a clear oil. IR (CHCl₃):3240 cm⁻¹ ; ¹ H NMR (CDCl₃) δ4.85 (2H, br s), 8.12 ppm (1H, br s). Asolution of 0.9 g (2.34 mmol) of the imidate in 20 mL of xylene wasrefluxed for 9 hours. The homogeneous solution was cooled and directlypurified on 100 g of silica gel (ethyl acetate:hexane, 1:4) to afford0.29 g of starting material. Further elution produced 0.17 g of theabove trichloroacetamide 21 as a solid. mp 178.0°-179.020 0 C.(ether/dichloromethane). ¹ H NMR (CDCl₃) δ4.49 (1H, m), 5.12 ppm (2H, brd).

EXAMPLE 17 hexahydro-5α-(hydroxymethyl)-4β-(trichloroacetyl)amino!-1H-3a.beta.,6aβ-cyclopenta c!pyrrole 22##STR18##

To a solution of 0.16 g (0.41 mmol) of trichloroacetamide 21 fromExample 16 in 5 mL of tetrahydrofuran was added via syringe a 1.0Msolution of borane/tetrahydrofuran (1.03 ml, 1.03 mmol) complex intetrahydrofuran. The clear homogeneous solution was stirred for 2 hoursat which time it was treated with 10 mL of a 10% aqueous solution ofsodium acetate followed by 1.1 mL of a 30% aqueous solution of hydrogenperoxide. After stirring for 3 hours, the solution was extracted withethyl acetate (4×20 mL). All organic extracts were combined, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure. Filtration through 50 g of silica gel (ethyl acetate) provided85 mg of diastereomeric alcohols as an oil. Chromatography on 50 g ofsilica gel (ethyl acetate:hexane, 2:3) provided 25 mg of the syndiastereomer as an oil. Further elution gave 10 mg of the anti alcohol22 as an oil. ¹ H NMR (CDCl₃) δ3.69 (2H, m), 3.82 ppm (1H, m).

EXAMPLE 18 N-(hexahydro-1H-2,5β-methano-3aα,6aα-cyclopentac!pyrrol-4α-yl)amine 11 ##STR19##

To a solution of 7 mg (0.018 mmol) of anti alcohol from Example 17 in 2mL of pyridine at 0° C. was added 20 mg (0.105 mmol) ofp-toluenesulfonyl chloride. The homogeneous solution was allowed tostand overnight at 5° C. The solution was concentrated under reducedpressure. The solid residue was taken up in 5 mL of water and extractedwith ether (2×5 mL). All organic extracts were combined, washed with asaturated aqueous solution of copper (II) sulfate (2×5 mL), washed with5 mL of brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to afford 6 mg of crude tosylate asan oil. A solution of the tosylate in 3 mL of trifluoroacetic acid wasstirred at 0° C. for 30 min, removed from the ice water bath, andstirred for an additional 30 min. The clear homogeneous solution wasconcentrated under reduced pressure. The resulting oil was dissolved in4 mL of dimethylformamide and treated with 0.1 mL ofdiisopropylethylamine. The solution was stirred for 48 hours at whichtime it was concentrated under reduced pressure. The residue was takenup in 5 mL of a 10% aqueous solution of potassium carbonate andextracted with chloroform (3×5 mL). All organic extracts were combined,dried over anhydrous potassium carbonate, filtered, and concentratedunder reduced pressure. The brown oil was chromatographed on 0.5 g ofsilica gel (chloroform:methanol:ammonium hydroxide, 85:15:1) to produce2 mg of the tetracycle 11. ¹ H NMR (CDCl₃) δ2.78 (4H, m), 2.99 (4H, m),3.32 (1H, br s), 3.50 (2H, br t). ¹³ C NMR (CDCl₃) 37.68, 38.31 41.93,45.56, 64.73, 65.29, 66.48, 69.83 ppm. ##STR20##

The reaction Scheme III further illustrates a portion of the reactionsequence herein. With respect to reaction Scheme III, methylphenylsulfonyl acetate is reacted to produce an allylated acetate 23.The allylated acetate is reacted with N-iodosuccinimide to produce aniodinated phenylsulfonyl acetate 24. The iodinated phenylsulfonylacetate 24 can be reacted to produce the bicyclic compound 25 byreaction with N--BOC allylamine. Reductive elimination of 25 to thebicycloamine 6 offers an alternative approach to this intermediatepreviously described in Scheme I. The following examples 19-24 furtherillustrate the reaction sequence shown in Scheme III.

EXAMPLE 19 but-3-en-1-carbomethoxy-1-yl-phenylsulfone 23 ##STR21##

To a suspension of 2.15 g (53.8 mmol) of sodium hydride in 350 mL oftetrahydrofuran at 0° C. was added via cannula a solution of 9.6 g (44.8mmol) of methyl phenylsulfonyl acetate in 50 mL of tetrahydrofuran. Thehomogeneous solution was warmed to room temperature and stirred for 15min. The resulting white suspension was treated with 5.4 g (44.8 mmol)of allyl bromide. After stirring for 20 hours, the mixture was dilutedwith 100 mL of water and extracted with ethyl acetate (3×200 mL). Allorganic extracts were combined, dried over anhydrous magnesium sulfate,filtered, and concentrated under reduced pressure to provide 11.5 g ofcrude product. Chromatography on a Waters Prep 500 system (ethylacetate:hexane 7:93 to 12:88; flow rate 200 mL/min) afforded 6.86 g ofalkylated acetate 23 as an oil. ¹ H NMR (CDCl₃) δ2.72 (2H, m), 3.68 (3H,s), 4.02 (1H, dd, J=11.0, 4.0 Hz), 5.13 (2H, m), 5.67 (1H, m), 7.60 (2H,t, J=9.0 Hz), 7.71 (1H, t, J=8.5 Hz), 7.89 (2H, d, J=8.8 Hz). Anal.calcd for C₁₂ H₁₄ O₄ S: C, 56.68; H, 5.56; found: C, 56.37; H, 5.54

EXAMPLE 20 2-(1,1-dimethylethyl)-5-methylhexahydro-3aβ, 6aβ-cyclopentac!pyrrole-5-(phenylsulfonyl)-2,5(1H,4H)-dicarboxylate 25 ##STR22##

To a suspension of 50 mg (1.23 mmol) of sodium hydride in 25 mL oftetrahydrofuran was added 0.285 g (1.12 mmol) of the sulfone 23 fromExample 19. After stirring for 30 min, the clear mixture was treated viacannula with a solution of 0.25 g (1.12 mmol) of N-iodosuccinimide in 10mL of tetrahydrofuran. The resulting suspension was stirred in the darkfor 1 hour at which time it was directly purified on 75 g of silica gel(ether) to provide 0.38 g of labile iodosulfonyl acetate 24 as an orangebrown oil. To a solution of 0.38 g (0.92 mmol) of iodosulfonyl acetate24 and 0.29 g (1.85 mmol) of N--BOC allylamine in 3 mL of benzene wasadded via syringe 0.054 mL (0.14 mmol) of bis(tributyltin). The clearhomogeneous solution was exposed to light from a sunlamp (d=8 cm) for 30min at which time the light source was removed and 1.5 mL oftriethylamine was added. The resulting red-brown homogeneous solutionwas heated to reflux for 14 hours. The suspension was concentrated underreduced pressure and filtered through 50 g of silica gel (ethylacetate:hexane, 1:1) to provide a brown oil. Medium pressure liquidchromatography (ethyl acetate:hexane, 1:2; flow rate 8 mL/min; 15×1000mm column) afforded 0.17 g of bicycle 25 as an oil. ¹³ C NMR (CDCl₃)27.2, 35.1, 36.3, 40.4, 40.7, 48.7, 49.5, 52.1, 78.5, 79.0, 127.9,128.4, 133.2, 136.0, 153.8, 167.5 ppm. MS for C₂₀ H₂₇ NO₆ S: M⁺¹ 410.

EXAMPLE 212-(1,1-dimethylethyl)-5-(phenylsulfonyl)-5-(formyl)-hexahydro-3-aβ,6aβ-cyclopenta c!pyrrole-2(1H)-carboxylate 26 ##STR23##

To a solution of 3.6 g (8.84 mmol) of bicycle 25 from Example 20 in 100mL of dichloromethane at -78° C. was added via syringe 20.6 mL (20.6mmol) of a 1.0M solution of diisobutylaluminum hydride indichloromethane. After stirring for 1 hour at -78° C., the solution wasquenched with 3 mL of methanol and poured into 800 mL of a saturatedaqueous solution of Rochelle's salt. The mixture was stirred overnightand extracted with chloroform (4×500 mL). All organic extracts werecombined, dried over anhydrous potassium carbonate, filtered, andconcentrated under reduced pressure to provide 3.1 g of the abovealdehyde 26 as an oil ¹ H NMR (CDCl₃) δ9.72 (1H, s).

EXAMPLE 222-(1,1-dimethyl)-5-(phenylsulfonyl)-5-(hydroxymethyl)-hexahydro-3aβ,6aβ-cyclopentac!pyrrole-2(1H)-carboxylate 27 ##STR24##

To a solution of 3.1 g (8.06 mmol) of aldehyde 26 from Example 21 in 35mL of tetrahydrofuran at 0° C. was added via syringe 6.05 mL (12.1 mmol)of a 2.0M solution of lithium borohydride in tetrahydrofuran. Afterstirring at 0° C. for 1 hour, the clear homogeneous solution wascarefully quenched with 15 mL of a 2% aqueous solution of hydrochloricacid and poured into 50 mL of water. The mixture was extracted withether (3×100 mL). All organic extracts were combined, dried overanhydrous magnesium sulfate, filtered, and concentrated under reducedpressure to afford 3.09 g of a solid. Recrystallization from etherafforded analytically pure alcohol 27, mp 126.0°-127.0°C. Anal. calcdfor C₁₉ H₂₇ NO₅ S: C, 59.82; H, 7.15; N, 3.67; found: C, 59.58; H, 7.14;N, 3.58.

EXAMPLE 232-(1,1-dimethyl)-5-(phenylsulfonyl)-5-(acetoxymethyl)-hexahydro-3aβ,6aβ-cyclopentac!pyrrole-2(1H)-carboxylate 28 ##STR25##

To a solution of 3.27 g (8.57 mmol) of alcohol 27 from Example 22 and2.1 mL (25.7 mmol) of pyridine in 40 mL of tetrahydrofuran was added 0.9mL (12.9 mmol) of acetyl chloride. The suspension was stirred for 18hours at which time it was concentrated under reduced pressure. Thesolid was dissolved in 50 mL of water and extracted with ether (4×50mL). All organic extracts were combined, washed with a saturated aqueoussolution of copper(II) sulfate (2×50 mL), washed with 50 mL of brine,dried over anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. Chromatography on 100 g of silica gel (ethylacetate:hexane, 2:3) provided 3.24 g of the above acetate 28 as a foam.¹ H NMR (CDCl₃) δ1.64 (9H, s), 4.16 (2H, s), 7.47 (2H, t, J=8 Hz), 7.58(1H, t, J=7.5 Hz), 7.78 (2H, d, J=7.5 Hz). Anal. calcd for C₂₁ H₂₉ NO₆S: C, 59.55; H, 6.92; N, 3.31; found: C, 58.94; H, 7.01; N, 3.09.

EXAMPLE 24 cis-1,1-dimethylethylhexahydro-5-methylenecyclopentac!pyrrole-2(1H)-carboxylate 6 ##STR26##

To a solution of 0.34 g (0.8 mmol) of acetate 28 from Example 23 in 21mL of tetrahydrofuran and 7 mL of methanol at 20° C. was added 17.7 g ofpulverized 2.5% sodium amalgam. The mixture was stirred at -20° C. for 3hours, warmed to 10° C. and diluted with 75 mL of water The mixture wasdecanted and filtered. The filtrate was extracted with ether (4×50 mL).The organic extracts were combined, dried over anhydrous magnesiumsulfate, filtered, and concentrated under reduced pressure.Chromatography on 20 g of silica gel (ethyl acetate:hexane; 1:4)provided 0.1 g of the above alkene 6 as an oil. This product wasidentical in all aspects to alkene 6 of Example 5 synthesized by thealternate scheme.

The following reaction Scheme IV illustrates another method forproducing tetracyclic benzamides. In the reaction sequence shown inScheme IV a compound 8 is oxidized with pyridinium dichromate (PDC) toproduce the compound 23. The compound 23 is reacted to produce compound24. Compound 24 is reacted to produce the tetracycle 25 which can bereductively cleaved to produce the tetracycle 26. The tetracyle 26 canbe reacted with a benzamide 12 to produce the tetracycle benzamide 27which can be deprotected with base followed by treatment with HCl toproduce the benzamide tetracycle hydrochloride 28. The Example 25following the reaction Scheme IV is illustrative of the reactionsequence shown in the reaction Scheme IV. ##STR27##

EXAMPLE 25 4-methyl-N-(hexahydro-1H-2,5β-ethano-3aα,6aα-cyclopentac!pyrrole-4α-yl)benzenesulfonamide 26 ##STR28##

The previously described alcohol 8 is oxidized with pyridiniumchlorochromate to afford the aldehyde 23. Wittig olefination (Ph₃ PCH₂)of the aldehyde 23, followed by hydroboration/oxidation (BH₃ /THF; thenH₂ O₂ /NaOH) gives the homologated alcohol 24. Tosylation, deprotection,and closure performed in a manner as set forth in Examples 8 and 9yields the desired compound 25 Reductive removal (Na/NH₃) of the tosylprotecting group yields the tetracycle 26.

The indoles, benzofurans, benzothiophenes, indenes, benzimidazoles andindazoles can be formed by the following reaction sequence wherein m canbe 1 or 2 depending upon which tetracycle is to be formed. ##STR29##

EXAMPLE 26 (±)-N-(hexahydro-1H-2,5β-methanol-3aα,6aα- cyclopentac!pyrrol-4α-yl)-1H-indole-3-carboxamide, monohydrochloride ##STR30##

To a solution of indole-3-carboxylic acid (64 mg, 0.40 mmol) in DMF (1ml) was added carbonyldiimidazole (64 mg, 0.40 mmol). After stirring for4.5h at room temperature a solution of azatetracycle 11 (52 mg, 0.38mmol) in DMF (2 ml) was added dropwise and the reaction was stirred for40h at room temperature. Concentration in vacuo gave a residue which wasextracted with ethyl acetate (4×) after the addition of 3 ml of 1N KOH.The combined organic extracts were washed with water (3×) and brine andthen dried with Na₂ SO₄. Concentration in vacuo gave a colorless solid(95 mg) which was chromatographed on silica gel eluting withmethanol/chloroform/ammonium hydroxide (9.5/90/0.5) to give the desiredamide (40 mg, 38%) as a colorless powder.

This amide in methanol (0.5 ml) was treated with HCl/methanol preparedfrom acetyl chloride (9.5 mg, 0.12 mmol) and methanol (0.5 ml)!. Theresulting salt was crystallized from methanol/diethyl ether to give thetitle compound (28 mg) as a colorless powder: mp 324°-325° C. (dec).Anal. calcd for C₁₇ H₁₉ N₃ O.HCl.1/4H₂ O: C,63.35; H, 6.41; N, 13.04.found: C, 63.65; H, 6.41; N, 12.88. MS calcd for C₁₇ H₁₉ N₃ O: 281.1528;found: 281.1528.

EXAMPLE 27 (±)-N-(hexahydro-1H-2,5β-methano-3aα,6aα-cyclopentac!pyrrol-4α-yl)-1-methyl-1H-indazole-3-carboxamide, hydrochloride##STR31##

To a solution of N-methylindazole-3-carboxylic acid (83 mg, 0.47 mmol;prepared by the method of Fludzinski (J. Med. Chem., Vol. 30, 1535,1987) in DMF (1 ml) was added carbonyldiimidazole (76 mg, 0.47 mmol).After stirring for 3h at room temperature a solution of azatetracycle 11(65 mg, 0.47 mmol) in DMF (2 ml) was added dropwise. The resultingsuspension was stirred for 20h at room temperature, then heated to 65°C. for 1.5h. The reaction mixture was then concentrated under a streamof nitrogen. To the residue was added 1N KOH (5ml) followed byextractions with chloroform (5×). The combined organic extracts werewashed with water (4×) and brine, dried (Na₂ SO₄), and concentrated invacuo to give a pale yellow foam (145 mg).

Purification on silica gel eluting with methanol (saturated withammonia)/chloroform (3/97) gave the desired amide (89 mg, 64%) free baseas a colorless powder: mp 186.5°-187° C. To a solution of this material(85.3 mg, 0.288 mmol) in methanol (0.5 ml) was added a solution of HClin methanol made from acetyl chloride (25 mg, 0.32 mmol) and methanol(0.5 ml)!. Crystallization from methanol/diethyl ether gave the titlecompound (92.5 mg) as a colorless powder: mp 141°-149° C. Anal calcd forC₁₇ H₂₀ N₄ O.1.1HCl.1.1H₂ O: C, 57.31; H, 6.59; N, 15.73; Cl, 10.95.Found: C, 57.35; H, 6.59; N, 15.48; Cl, 10.81. MS calcd for C₁₇ H₂₀ N₄ O296.1640; found: 296.1628.

The method for the synthesis of compounds wherein Ar is ##STR32## Isshown by the following reaction sequence. ##STR33##

The aromatic moiety can be synthesized in the matter disclosed inAustralian patent application AU8207867 (beginning at about page 14thereof). The coupling of the tetracyclic moiety to the aromatic moietycan be performed in the manner as taught in the Australian patentapplication AU 8207867.

For the synthesis of compounds wherein the aromatic moiety has thefollowing structure ##STR34##

The method disclosed in European patent application 88310208.9 havingpublication no. 0315390A2 beginning at about page 6 thereof for makingthe aromatic moiety and bonding a cyclic moiety to such aromatic moietycan be used but using the tetracyclic moieties herein described.

A synthesis of compounds wherein the aromatic moiety has the followingstructure as is described in Australian Patent 8767121 ##STR35## can bereacted in the reaction sequence using the techniques described in theAustralian Patent to bond the cyclic moiety therein but using thetetracyclic moieties described herein. ##STR36##

The method for the coupling procedure is shown in Australian patentapplication 8767121 beginning at about page 8 thereof.

The azatetracyclic alcohols 32 and 35 are prepared according to SchemeV. Thus treatment of the previously described olefin 6 with seleniumdioxide, followed by alcohol protection gives the silylated ether 29.Hydroboration (thexyl borane) of the ether 29 gives the alcohol 30.Treatment of the alcohol 30 with tosyl chloride, followed bytrifluoroacetic acid and Hunig's base affords the protected tetracycle31. Removal of the silyl protecting group (Bu₄ NF/THF) gives the desiredazatetracyclic alcohol 32.

Alternatively, treatment of compound 30 with pyridinium chlorochromate(PCC), followed by Wittig olefination (Ph₃ PCH₂) and hydroboration (BH₃/THF) gives the homologated alcohol 33. Treatment of the alcohol 33 withtosyl chloride, followed by trifluoroacetic acid and Hunig's baseaffords the protected tetracycle 34. Removal of the silyl protectinggroup (Bu₄ NF/THF) gives the desired azatetracyclic alcohol 35.##STR37##

The compounds of formula I wherein p is one, A is NH and B is NH or Ocan be prepared in accordance with the procedures described in U.S. Pat.No. 4,797,387 the entire disclosure of which is incorporated herein bythis reference. As shown in the following reaction Scheme VI a compound36 is reacted with H--BD (compound 11, 26, 32, or 35) to give thedesired compound of formula I. When A' is H, then B' is COL₁ wherein L₁is a group displaceable by H--BD. Examples of L₁ include chloro, bromo,C₁₋₄ alkoxy, PhO--, or Cl₃ CO--. The reactions are preferably performedin an inert nonhydroxylic solvent such as benzene, methylene chloride,toluene, diethyl ether, tetrahydrofuran (THF), or dimethylformamide(DMF). It is also preferable to perform the reaction in the presence ofan acid acceptor such as triethylamine, pyridine, calcium carbonate,sodium carbonate, or potassium carbonate. Optionally, A' and B' togethercan be ═C═O, wherein H--BD is reacted with the compound 29 in an inertsolvent as described above.

Alternatively, the compounds of formula I wherein p is 1, A is NH and Bis NH or 0 can be prepared by treating ArNH₂ (37) with compounds offormula 38 (an isocyanate or activated carbonyl derivative ofazatetracycles 11, 26, 32 or 35). L₁ is as described above. The reactionis performed in a nonhydroxylic solvent such as methylene chloride, THF,or DMF and preferably in the presence of an acid acceptor as identifiedabove. ##STR38##

The compounds herein have been found to be useful for treatinggastrointestinal motility disorders in mammals. Their usefulness hasbeen shown by their demonstrated prokinetic activity. Prokineticactivity of a compound can be determined by measuring the enhancement ofgastric emptying of a meal in a rat model to which the compound has beenadministered. This method for determining prokinetic activity of acompound has been described by Droppleman, et al, J. Pharmacol. andMethods 4: 227-230 (1980).

The compounds herein exhibit 5-HT3 antagonism. 5-HT3 antagonism can bedetermined in a model of emesis induced by the chemotherapeutic agentcisplatin as described herein.

Antiemetic Activity

Antiemetic activity of test compound against cisplatin was determined inbeagle dogs. Dogs are pretreated I.V. with a test compound dissolved inDMSO thirty minutes before administration of cisplatin 3 mg/kg.i.v. witha second dose of compounds given i.v. two hours after cisplatinadministration. Emetic episodes are counted for 5 hours followingcisplatin administration. The latency for first emesis and the number ofemetic episodes for test compounds are compared with results for controltreatment (vehicle).

Percent inhibition of emesis for each animal is determined by thefollowing formula: ##EQU1## A mean inhibitory dose (ID₅₀) which resultsin 50% inhibition of the number of emetic episodes is determined.

Antiemetic activity of a representative compound was demonstrated asshown by the results in the following Table II which includes resultsfor BRL 24924, cisapride and ICS 205-930.

                  TABLE II    ______________________________________    COMPOUND           ID.sub.50 (mg/kg iv)    Example 12         0.03    Example 27         0.10 (72%                       inhibition)    BRL-24924          0.10    Cisapride          0.6    ICS 205-930        0.01    ______________________________________

Rat Gastric Emptying Protocol

A test meal for measuring gastric emptying in rats was prepared. Tengrams of methylcellulose (2% solution=15 centipoises; Aldrich ChemicalCompany, Milwaukee, Wis.) was added to 200ml of cold water and mixed at20,000 rpm in a Waring blender to insure dispersion and hydration of themethylcellulose. In addition, two beef bouillon cubes (Wyler's,Columbus, Ohio) dissolved in 100ml of warm water was added to themixture, followed by 16g of casein (Hammersten, Schwartz/Mann,Orangeburg, N.Y.), 8g of powdered confectioners sugar and 8g ofcornstarch. The ingredients were mixed for two minutes at 20,000 rpm andthe resultant test meal was refrigerated for 48 hours to allow trappedair to escape. Male Charles River Rats, Crl: COBS, CD (SD) BR Strain,180-200g body weight, were used in groups of six animals. The animalswere food deprived for 24 hours prior to the experiment with access towater ad libitum. The compounds to be evaluated were prepared in a 0.5%aqueous methylcellulose solution. If insoluble, the mixture washomogenized for two minutes at 5500 rpm using a Try-R-Stir-R. Thecompounds were injected intraperitoneally at a volume of 5ml/kg, 30minutes before the test meal, (3.0ml/rat i.g.). Control animals receivedonly the vehicle. Sixty minutes after the test meal, the rats weresacrificed by cervical dislocation. The stomachs were removed intact andweighed. The stomachs were kept opened, gently rinsed with tap water,blotted dry with paper towelling, and the empty stomach weighed. Thedifference between the weight of the full and empty stomach isindicative of the amount of meal remaining in the stomach. The amount ofmeal remaining in the stomach was subtracted from the weight of 3ml ofthe test meal to determine the amount of food emptied from the stomachduring the test. Weight of the test meal was determined by weighingthree samples (3ml) at the beginning and three samples at the end ofeach experiment and calculating the mean. The mean and standard error ofthe amount of meal emptied were calculated.

The results of following the protocol and comparing representativecompounds herein to known prokinetic agents, metoclopramide andcisapride, are shown in Table III.

                  TABLE III    ______________________________________                  DOSE      % INCREASE IN    COMPOUND      (mg/kg ip)                            GASTRIC EMPTYING    ______________________________________    EXAMPLE 12    0.001     -5.8                  0.01      2.0                  0.03      16.4                  0.1       31.3                  0.3       32.1                  1.0       45.3    BRL-24924     1.0       29.8                  3.0       34.2                  10.0      35.2    METOCLOPRAMIDE                  1.0       2.6                  3.0       11.2                  10.0      34.1    CISAPRIDE     1.0       9.8                  3.0       15.4                  10.0      25.0    ZACOPRIDE     0.3       1.4                  1.0       11.8                  3.0       9.3                  10.0      18.5                  30.0      6.3    ______________________________________

We claim:
 1. A compound of the formula ##STR39## wherein D is ##STR40##wherein B is NH or O; wherein A is NH or a bond;wherein p is 1 or 0; andwhen p is 1, Ar is ##STR41## and when p is 0, Ar is ##STR42## wherein Xis O,S,N(R⁴) or CH₂ ; wherein Y is N or CH; wherein n is 1 or 2; whereinZ is ##STR43## wherein R¹ is alkoxy of 1 to 6 carbon atoms; wherein R²and R³ are the same or different and is hydrogen, halogen, CF₃,hydroxyl, C₁₋₂ alkoxy, C₂₋₇ acyl, amino, amino substituted by one or twoC₁₋₆ alkyl groups, C₂₋₇ acyl amino, amino carbonyl, or amino sulfoneoptionally substituted by one or two C₁₋₆ alkyl groups, C₁₋₆ alkylsulfone or nitro groups; wherein R⁴ and R⁴ ' can be the same ordifferent and is hydrogen, alkyl or arylalkyl; wherein R⁵ and R⁶ is thesame or different and is hydrogen, halogen, CF₃, C₁₋₆ alkyl, C₁₋₇ acyl,C₁₋₇ acylamino, or amino, amino carbonyl or amino sulfonyl, optionallysubstituted by one or two C₁₋₆ alkyl or C₃₋₈ cycloalkyl groups, or byC₄₋₅ polymethylene or biphenyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfinyl,C₁₋₆ alkoxy, C₁₋₆ alkylthio, hydroxy or nitro or when R⁵ and R⁶ aretaken together are methylenedioxy or ethylenedioxy; wherein R⁹ and R¹⁰can be the same or different and is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₄ alkynyl or together are C₂₋₄ polymethylene; wherein R⁷ and R⁸ arethe same or different and is hydrogen, halogen, CF₃, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ alkylthio, C₁₋₇ acyl, C₁₋₇ acylamino, C₁₋₆alkylsulfonylamino, N-(C₁₋₆ alkylsulfonyl)-N-C₁₋₄ alkylamino, C₁₋₆alkylsulfinyl, hydroxy, nitro or amino, aminocarbonyl, aminosulfonyl,aminosulfonylamino or N-(aminosulfonyl)-C₁₋₄ alkylamino optionallyN'-substituted by one or two groups selected from C₁₋₆ alkyl, C₃₋₈cycloalkyl, phenyl, or phenyl C₁₋₄ alkyl groups or optionallyN'-disubstituted by C₄₋₅ polymethylene; and wherein R¹¹ and R¹² can bethe same or different and is hydrogen or C₁₋₄ alkyl or taken togetherare a covalent bond; andwherein R¹³ is H, halogen or OR⁴.
 2. A compoundas recited in claim 1 wherein D is ##STR44##
 3. A compound as recited inclaim 2 wherein p is
 1. 4. A compound as recited in claim 3 wherein B isNH.
 5. A compound as recited in claim 4 wherein A is a covalent bond. 6.A compound as recited in claim 5 wherein Ar is ##STR45##
 7. A compoundas recited in claim 6 whereinR₁ is methoxy; R₂ is amino; and R₃ ischloro.
 8. A compound as recited in claim 7 having the structure##STR46##
 9. A compound as recited in claim 5 wherein Ar is ##STR47##10. A compound as recited in claim 9 wherein X is NH.
 11. A compound asrecited in claim 5 wherein Ar is ##STR48##
 12. A compound as recited inclaim 5 wherein Ar is ##STR49##
 13. A compound as recited in claim 12wherein R⁴ is a methyl group.
 14. A compound as recited in claim 5wherein Ar is ##STR50##
 15. A compound as recited in claim 4 wherein Ais NH.
 16. A compound as recited in claim 15 wherein Ar is ##STR51## 17.A compound as recited in claim 15 wherein Ar is ##STR52##
 18. A compoundas recited in claim 15 wherein Ar is ##STR53##
 19. A compound as recitedin claim 15 wherein Ar is ##STR54##
 20. A compound as recited in claim15 wherein Ar is ##STR55##
 21. A compound as recited in claim 3 whereinB is
 0. 22. A compound as recited in claim 2 wherein p is
 0. 23. Acompound as recited in claim 22 wherein Ar is ##STR56##
 24. A compoundas recited in claim 22 wherein Ar is ##STR57##
 25. A compound as recitedin claim 1 wherein D is ##STR58##
 26. A compound as recited in claim 25wherein p is
 1. 27. A compound as recited in claim 26 wherein B is NH.28. A compound as recited in claim 27 wherein A is a covalent bond. 29.A compound as recited in claim 28 wherein Ar is ##STR59##
 30. A compoundas recited in claim 29 whereinR₁ is methoxy; R₂ is amino; and R₃ ischloro.
 31. A compound as recited in claim 28 wherein Ar is ##STR60##32. A compound as recited in claim 28 wherein Ar is ##STR61##
 33. Acompound as recited in claim 28 wherein Ar is ##STR62##
 34. A compoundas recited in claim 28 wherein Ar is ##STR63##
 35. A compound as recitedin claim 27 wherein A is NH.
 36. ##STR64##
 37. A compound as recited inclaim 35 wherein Ar is ##STR65##
 38. A compound as recited in claim 35wherein Ar is ##STR66##
 39. A compound as recited in claim 35 wherein Aris ##STR67##
 40. A compound as recited in claim 35 wherein Ar is##STR68##
 41. A compound as recited in claim 26 wherein B is
 0. 42. Acompound as recited in claim 25 wherein p is
 0. 43. A compound asrecited in claim 42 wherein Ar is ##STR69##
 44. A compound as recited inclaim 42 wherein Ar is ##STR70##
 45. A pharmaceutical compositioncomprising therapeutically or prophylactically effective amount of acompound of claim 1 of the formula ##STR71## and a pharmaceuticalcarrier.
 46. A pharmaceutical composition as recited in claim 45 whereinD is ##STR72##
 47. A pharmaceutical composition as recited in claim 45wherein D is ##STR73##
 48. A method of treating gastrointestinalmotility disorders comprising administering to a patient in need of suchtreatment, a therapeutically effective amount of a compound according toclaim 2 and a pharmaceutically acceptable carrier.
 49. A method oftreating gastrointestinal motility disorders comprising administering toa patient in need of such treatment, a therapeutically effective amountof a compound according to claim 25 and a pharmaceutically acceptablecarrier.
 50. A method of preventing emesis or ileus comprisingadministering to a patient in need of such treatment, a therapeuticallyeffective amount of a compound according to claim 2 in apharmaceutically acceptable carrier.
 51. A method for preventing emesisor ileus comprising administering to a patient in need of suchtreatment, a therapeutically effective amount of a compound according toclaim 25 in a pharmaceutically acceptable carrier.
 52. A method oftreating emesis, anxiety, pain, schizophrenia, depression, substanceabuse, memory impairment, or related diseases having a serotonergicetiology benefiting from use of a serotonergic 5-HT₃ antagonistcomprising administering to a patient in need of such treatment, atherapeutically effective amount of a compound according to claim 2 anda pharmaceutically acceptable carrier.